Phase I/II trial of S65487 plus azacitidine in acute myeloid leukemia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut De Recherches Internationales Servier IRIS

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

25 Feb 2021 → 28 Mar 2026

Decision date (initial)

2024-06-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

ADIR France · Laboratorio Servier S.L.

External identifiers

EU CT number

2023-510051-27-00

EudraCT number

2020-003061-19

ClinicalTrials.gov

NCT04742101

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenomic, Pharmacodynamic, Safety, Efficacy, Dose response, Pharmacokinetic

1. Phase I: To determine the safety profile and tolerability of S65487 combined with azacitidine (including Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD)).
2. Phase I: To determine the Recommended Phase II Dose (RP2D) of S65487 combined with azacitidine
3. Phase II: To assess the efficacy of S65487 combined with azacitidine

Secondary objectives 6

1. Phase I: To determine the PK parameters of S65487 and azacitidine administered in combination and of potential metabolites (if applicable)
2. Phase I: To assess the anti-leukemic activity of S65487 combined with azacitidine
3. Phase II: To assess anti-leukemic activity of S65487 combined with azacitidine
4. Phase II: To evaluate the depth and the duration of response
5. Phase II: Safety profile and tolerability of S65487 in combination with azacitidine
6. Phase II: To determine the PK parameters of S65487 and azacitidine administered in combination and of potential metabolites (if applicable)

Conditions and MedDRA coding

Acute Myeloid Leukemia (AML)

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. 1. Male or female participant aged ≥ 18 years
2. 2. Participants with cytologically confirmed and documented treatment naïve, de novo or secondary AML defined by WHO 2016 classification (Arber, 2016). Secondary AML includes: a. Previous myelodysplastic syndrome transformed b. AML due to exposure to potentially leukemogenic therapies or agents (e.g. radiation therapy, alkylating agents, topoisomerase II inhibitors) with the primary malignancy in remission for at least 3 years
3. 3. Participants not eligible for standard induction chemotherapy a. Aged ≥ 75 years old b. Or Age ≥18 years with at least one of the following comorbidities: i. Clinically significant heart or lung comorbidities, as reflected by at least one of: - Lung diffusing capacity for carbon monoxide (DLCO) ≤65% of expected - Forced expiratory volume in 1 second (FEV1) ≤65% of expected ii. Other contraindication(s) to anthracycline therapy (must be documented) iii. Other comorbidity that the Investigator judges as incompatible with intensive remission induction chemotherapy, which must be documented
4. 4. ECOG (Eastern Cooperative Oncology Group) performance status should be (criterion should be rechecked at inclusion visit) ECOG ≤ 2.
5. 5. Written informed consent obtained prior any study specific procedure as described in section 13.3 of the protocol.
6. 6. Adequate renal and hepatic function
7. 7. Circulating White Blood Cell Count (WBC count) < 25*109 G/L (with or without use of hydroxycarbamide/leukapheresis)

Exclusion criteria 6

1. Major surgery within 3 weeks prior to the first IMP administration, or participants who have not recovered from side effects of the surgery
2. Any radiotherapy within 3 weeks before the first IMP administration, (except for palliative radiotherapy at localised lesions not considered as target lesions)
3. Allogenic stem cell transplant within 3 months before the first IMP administration and/or participants with active Graft-versus-host disease within 3 months before the first IMP administration and/or participants who still receive immunosuppressive treatment within 3 months before the first IMP administration and/or participant who receive donor lymphocyte infusion (DLI) within 3 months before the first IMP administration
4. Acute promyelocytic leukemia (APL, French-American-British M3 classification)
5. Favorable risk cytogenetics such as t(8;21), inv(16) or t(16;16) or t(15;17) as per the National Comprehensive Cancer Network (NCCN) Guidelines Version 3, 2019 for Acute Myeloid Leukemia
6. Previous treatment with hypomethylating agents (decitabine/azacitidine) or Bcl-2 inhibitors, particularly venetoclax for AHD (antecedent hematologic disorders)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. Phase I: DLT assessment at the end of cycle 1
2. Phase I: AE recording throughout the study evaluated according to CTCAE v5.0, dose interruptions, reductions, and intensity
3. Phase I: Vitals signs, Laboratory tests, ECG
4. Phase II: CR rate: Complete Remission (CR) rate.
5. Phase II: Antileukemic activity assessment using blood, bone marrow aspirate and bone marrow biopsies, if available, according to ELN 2022 response criteria and FDA

Secondary endpoints 4

1. For phase I: PK parameters of S65487, azacitidine and potential metabolite(s) if applicable will be determined in plasma (e.g. Cinf, tinf, AUClast, tlast, Clast, AUC, t½, z, CL and Vss)
2. For phase I: CR rate: Complete Remission (CR) rate, CR rate by initiation of cycle 2 (CR2), CR plus CRi rate: Complete Response rate with incomplete hematologic recovery, CR plus CRh rate: Complete Response with partial hematologic recovery, Duration of Response (DOR), Event Free Survival (EFS), Progression Free Survival (PFS), Overall Survival (OS), time to first response
3. For phase I: Antileukemic activity assessment using blood, bone marrow aspirate and medullary biopsies if available according to ELN 2022 response criteria and FDA
4. Phase II: CR plus CRi and CR plus CRh rate, CR by initiation of cycle 2, DOR, EFS, PFS, OS, time to first response, Minimal Residual Disease analysed centrally on pre- and on-treatment Bone marrow samples of participants at the same time as clinical response assessment. Incidence and severity of adverse events.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut De Recherches Internationales Servier IRIS

Sponsor organisation

Institut De Recherches Internationales Servier IRIS

Address

22 Route 128

City

Gif Sur Yvette

Postcode

91190

Country

France

Scientific contact point

Organisation

Institut De Recherches Internationales Servier IRIS

Contact name

Clinical Studies Department

Public contact point

Organisation

Institut De Recherches Internationales Servier IRIS

Contact name

Clinical Studies Department

Third parties 9

Locations

2 EU/EEA countries · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 29 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications